Mitochondria-Targeted Pyroptosis Orchestrated by Photodynamic Microneedle Patches Potentiates Melanoma Immunoradiotherapy.

Abstract

The lethality of melanoma stems from its high metastatic propensity, intrinsic apoptosis resistance, and a profoundly immunosuppressive microenvironment, which collectively undermine conventional radiotherapy and immunotherapy. Here, we develop a spatiotemporally precise therapeutic strategy using mitochondria-targeted photodynamic microneedles (mitoTPS-MNs) to orchestrate GSDME-mediated pyroptosis and potentiate systemic immunoradiotherapy. Upon transdermal photoactivation, mitoTPS induces intense, mitochondria-confined reactive oxygen species (ROS) bursts, triggering a caspase-3/GSDME-dependent pyroptotic cascade while simultaneously disrupting mitochondrial respiration to alleviate tumor hypoxia. This dual-action mechanism sensitizes melanoma to x-ray irradiation, achieving near-complete regression of primary tumors and remodeling "cold" tumor microenvironments into immunologically "hot" niches. The explosive release of damage-associated molecular patterns (DAMPs) from pyroptotic cells functions as an in situ cancer vaccine, promoting dendritic cell maturation, the systemic recruitment of CD8+ cytotoxic T lymphocytes, and potent abscopal responses against untreated distant metastases. Our work establishes mitochondria-directed pyroptosis as a mechanistic switch to bypass the inherent apoptotic resistance of melanoma, providing a clinically translatable strategy to convert localized interventions into systemic immunity against advanced melanoma.